Eisai Co., Ltd and Biogen Inc. announced today that Eisai presented new data for LEQEMBI® (lecanemab-irmb) 100 mg/mL injection for intravenous (IV) use, in the Late Breaking Symposium 4 Lecanemab for Early Alzheimer's Disease: Long-Term Outcomes, Predictive Biomarkers and Novel Subcutaneous Administration" at the 16th annual Clinical Trials on Alzheimer's Disease (CTAD) conference held in Boston, Massachusetts, United States and virtually October 24-27, 2023.
1. Subcutaneous Formulation Interim Data; Safety And Effects On Brain Amyloid
1) Weekly subcutaneous (SC) administration showed 14% greater amyloid plaque removal than biweekly IV administration as suggested in a preliminary analysis using amyloid PET at 6 months of treatment.
• The SC substudy, evaluating the SC formulation in an open-label extension (OLE) of the Clarity AD study*, included 72 patients who received LEQEMBI for the first time as the SC formulation, and 322 patients who received intravenous (IV) LEQEMBI in the Clarity AD core study followed by SC administration in this substudy. Reduction from baseline of amyloid in the brain by amyloid PET at 6 months in the newly treated SC patients by centiloid reduction was -40.3 ± 2.27 in SC administration compared to -35.4 ± 1.14 in IV administration.
2) SC Pharmacokinetics (AUC) Higher Than IV By 11%
• Weekly SC administration AUC are 11% higher than the biweekly IV formulation. 90% CI for drug exposure for SC vs. IV is within the bioequivalence limits of 80 to 125%. These data could allow Eisai to select a dose that achieves AUC that are comparable to the IV dose.
3) Lower Systemic Injection Reaction Rates With SC As Compared To IV
• Systemic injection/infusion reactions are uncommon and mild with SC administration, and in particular have not been observed in patients who received LEQEMBI for the first time as the SC formulation. There was a low rate of local injection site reactions (8.1%) in SC treated patients overall. Most were mild and moderate in severity consisting of redness, irritation, or swelling. No skin rash or other hypersensitivity reactions were reported.
4) ARIA Rates Of IV Formulation In Clarity AD Core Study Consistent With Rates In First-Time LEQEMBI Patients Entering The SC Substudy In Clarity AD OLE
• The incidence of ARIA-E with SC was similar to the IV. The incidences of ARIA-E, ARIA-H (cerebral microhemorrhage due to ARIA, cerebral hemorrhage, and brain surface hemosiderin deposition) and ARIA-H alone (ARIA-H without ARIA-E) with IV in the Clarity AD core study (n=898) were 12.6%, 17.3% and 8.9%, respectively. In newly treated patients in the SC substudy of the Clarity AD OLE (n=72), the incidences of ARIA-E, ARIA-H and ARIA-H alone were 16.7%, 22.2% and 8.3%, respectively. However, due to the sample size of newly treated patients in the SC substudy, no exact comparison can be made.
• Based on Phase II and III clinical studies, Cmax (maximum exposure) was the strongest predictor of ARIA-E incidence following IV administration. In the SC substudy, the steady-state exposure (AUCss) appears to be a better predictor of ARIA-E rates in the SC due to a relatively stable exposure profile.
Eisai aims to submit a LEQEMBI SC formulation Biologics License Application (BLA) with the U.S. Food and Drug Administration by March 31, 2024.
2. Latest Data From Tau Pet Longitudinal Substudy, Including A Post-Hoc Analysis Of The Low And Intermediate + High-Tau Subpopulations In The Clarity AD 18 Month Core Study
1) 76% of patients showed no decline and 60% showed clinical improvement at 18 months in low-tau / earlier stage early AD population.
• The Clarity AD study included an optional Tau PET substudy and used the tau PET probe MK6240** to identify patients with a low accumulation of tau in the brain, which represents the earlier stage of early AD.
• The low-tau subpopulation, which is in the earlier stages of early AD, is thought to show slow disease progression. In the low-tau subpopulation, 76% of the LEQEMBI group showed no deterioration and 60% showed clinical improvement after 18 months of treatment in the primary endpoint, Clinical Dementia Rating - Sum of Boxes (CDR-SB), compared with 55% and 28% of the placebo group, respectively.
• Importantly, in this low-tau subgroup, LEQEMBI treatment also showed consistent clinical response across multiple endpoints.*** In this population, LEQEMBI treatment favored cognition and function in the earlier stage of early AD.
• The efficacy results of the Tau PET substudy in the Clarity AD study, which observed tau pathology in the brain by tau PET, were consistent with overall results of the Clarity AD study.1
2) Tau PET Substudy Showed LEQEMBI Slows Development Of Tau Tangles In Early AD; Tau Spread In The Brain Is A Hallmark Of Disease Progression.
• In the Clarity AD Tau PET substudy, LEQEMBI treatment slowed the buildup of tau proteins in the temporal lobe (early Braak region), where tau accumulation was observed in the earlier stage of early AD. In the Tau PET substudy, LEQEMBI suppressed the accumulation of tau in the medial temporal brain region in low-tau subpopulations, and in a broader range of brain regions in the intermediate and higher accumulation groups**. This suggests that LEQEMBI treatment may have different effects on brain regions indexed by tau depending on the stage of the disease.1 The spread of tau in the brain is a hallmark of AD progression.
Efficacy Results From LEQEMBI Clarity AD Open-Label Extension Study
1) LEQEMBI Patients Continued to Show Benefit at 24 Months of Treatment
• In the 18-month core study of Clarity AD, there was a statistically significant difference in global cognition and function as measured by CDR-SB between the LEQEMBI and placebo groups. The separation in CDR-SB between the group that continued to receive LEQEMBI (early start group) and the group who switched from placebo to LEQEMBI (delayed start group) was maintained during the 6-month OLE following the core study. This indicates that similar disease trajectory for both early and delayed start groups occurred with LEQEMBI administration.
• The blood biomarker results (plasma Aβ42/40 ratio, ptau181, GFAP and NfL) showed improvement even after delayed initiation of treatment with LEQEMBI. These results suggest that LEQEMBI treatment may affect clinical outcomes through improvement of AD pathology.
The Mechanism-Based Rationale Of LEQEMBI Treatment In Early AD
1) Dual-Acting LEQEMBI3 Continues To Support Brain Neuron Function By Removing Highly Toxic Proteins (Protofibrils) That Can Cause Neuronal Injury And Death Even After Plaque Removal, Offering Patients The Opportunity For Continued Benefit.
• LEQEMBI has a unique dual action that binds more selectively to highly toxic protein (protofibrils) in addition to rapidly clearing plaque, and continues to support neuronal function by removing protofibrils that can cause neuronal injury and death after plaque has been cleared.
Protofibrils
• One of the AD pathological features is the accumulation of clusters (plaques) of amyloid beta (Aβ) in the brain. The formation of these plaques is the result of a continuous process by which individual Aβ proteins join together, latching onto each other, one at a time, like adding links to a chain. In the early part of this process these small chains of Aβ are soluble and are toxic to the nerves within the brain.
• The most toxic of the soluble chains is called a protofibril. Protofibrils are believed to contribute to the brain injury that occurs with AD and are considered to be the most toxic form of Aβ, having a primary role in the cognitive decline associated with this progressive, debilitating condition.
• Protofibrils cause injury to neurons in the brain, which in turn, can negatively impact cognitive function via multiple mechanisms, not only increasing the development of insoluble Aβ plaques but also increasing direct damage to brain cell membranes and the connections that transmit signals between nerve cells or nerve cells and other cells. It is believed the reduction of protofibrils may prevent the progression of AD by reducing damage to neurons in the brain and cognitive dysfunction.
